Process for the conversion of stereoisomers



United States Patent PROCESS FOR THE CONVERSION OF STEREOISOMERS RudolfRometsch, Riehen, Switzerland, assignor to Ciba Pharmaceutical ProductsInc., Summit, NJ.

No Drawing. ontinuation of application Ser. No. 476,846, Dec. 21, 1954,now Patent No. 2,838,519, dated June 10, 1958. This application Jan. 22,1958, Ser. No. 710,406

Claims priority, application Switzerland Dec. 23, 1953 6 Claims. c1.260-294) the formula CHC O'O CHa central nervous system and can be usedin states of fatigability, depression and exhaustion for instance inconvalescence, or combined with antihistaminics, for example withbenzyldimet-hylaminoethyl-aminopyridine, to counteract allergies.

The praent invention is based. on the observation that theu-arYI-a-piperidyI-(Z)-acetic acids obtainedl'by synthesis, and alsotheir functional acid derivatives, can be resolved into two racemates.As a result it was discovered that in the case of the ester racematesitis only .one of the two racemates which possesses the above specifiedtherapeutic properties, whereas the other is practically inactive.Moreover, it was possible to obtain the two optically active antipodesof the pharmacologically active racemates.

The pharmacologically active ester-racemates and their optically activeantipodes, as also the corresponding racemates and antipodes of theacids and acid derivatives, are hereinafter designated by the letter b,and generically referred [to as the b-stereo-isomeric form, byrepresenting the pharmacologically active ester-antipode not, the lessactive ester-antipode or the corresponding acids'or acid derivative. Theother racemates are called a-racemates and the corresponding antipodesare called-wantiare distinguished by a mild stimulating eitect onthepodes, or more exactly a,- and ayantipodes, andxthese forms aregenerically referredv to as! the a-stereoisomeric form.

The b antipode of a-phenyl-a-piperidyl-(2)-acetic acid methyl esterhydrochloride is 5 timesas active as the b antipode. V

A further feature of'the present invention comprisesa process for theconversion of the a-racematesora-antipodes into the racemates orantipodes of the b-series which are of value as medicaments, asdescribed above, or for the manufacture of such medicaments. ,Thisprocess consists in that the a-racemates" or aaantipodes. ofa-aryI-a-piperidyI-(Z) -acetic acids or their functional derivatives aretreated with alkaline agents, preferably at ice desired the b-racematesor b-antipodes isolated from the product which results and further, ifdesired, before or after the isolation, the free or functionallyconverted carboxyl group subjected to conversion.

As starting materials there can be used pure a-racemates, a-antipodes ora racemate mixture of a-aryl-upiperidyl-(2)-acetic acids or of theirfunctional acid derivatives such as esters, especially of low alkanols,primarily methanol, or also amides. As the aryl residue the phenylresidue is of particular importance and this may be substituted, forexample by a methoxy or methylene dioxy group. It is preferable to usethe a-racemates or a -antipodes of u-phenyl-u-piperidyl(2)-acetic acidor its functional derivatives. As alkaline agents there can be used. forexample alkali or alkaline earth hydroxides or alcoholates or strongorganic bases, as for example trimethyl-benzyl-arnmonium hydroxide,which are preferably used at elevated temperature.

Starting from a-racemates or racemate mixtures, mixtures of aandb-racemates are obtained. However, if a-antipodes are used, opticallyactive'products are obtained' instead of the expected racemates, in thatfrom a;- antipodes b' -antipodes of opposite rotation are formed andfrom the a -antipodes b -antipodes are obtained analogously. This showsthat, contrary to expectation the rearrangement in this process takesplace at only one of' the two asymmetrical carbon atoms.

The racemate mixtures to be used as starting materials can be made, forexample, by the process of the aforementioned US. Patent No. 2,507,631,filed March 9, 1945 by Max Hantmann et al. The a-antipodes can beobtained from the a-racemates bymeans of optically active tartaric acidby the usual methods.

The racemates and. antipodes of the a-aryl-ot-piperidyl- (2)-aceticacids or of their derivatives which are produced as products of thepresent process, especially the b racemate 'andfthe b -antipode ofa-phenyl-a-piperidyl- (2)-acetic acid methyl ester, can be used asmedicaments, as described above, or as intermediate products therefor.The ot-aryl-aapiperidyl-(2)acetic acids and the other functionalderivatives can be converted into the therapeutically useful esters. Thepresent invention also extends to pharmaceutical preparations whichcontain in.- admiicture' with a carrier material suitable fortherapeutic application, e.g. enteral or parenteral, preferably oral,administration of the racemates of an u-aryl-ix-piperidyl- (2)-aceticacid ester only the b-racemate. It also comprises such. preparations ascontain a b -antipode. In these preparations the content of b-racemateor b -antipode per unit. dose advantageous-1 y amounts to at least 1 mg.and at most 50 mg. As carrier materials such substances are concerned asdo not react with the new compounds, as for example water, gelatin,lactose, starch, magnesuim stearate, talc, vegetable oils, benzylalcohols, gum, polyalkyline glycols, petroleum jelly cholesterol orother known medicament'ca-rriers. The pharmaceutical preparations can,for example, be made up as tablets, dragees, salves, creams or in liquidform as solutions, suspensions or emulsions". They may, if desired, besterilized and/ormay contain auxiliary substances, such as preserving,stabilizing; wetting or emulsifying agents or salts which have theeifect of varying the osmotic pressure or also buffer substances. Theymay also contain other substances of therapeutic value eg.antihistaminics, suchas benzyl-dimethylaminoethyl-amino-pyridine. Thesepharmaceutical preparations-are produced by the conan elevatedtemperature, eLg. C.' to 1 20 .C.,

ventional methods.

This is a continuation of my copending application Serial'No. 476,846,filed December 21, 1954, now Patent No. 2,838,519.

The followingiexamples illustrate theinvention, the re- 3 lation betweenpart by weight and part by volume being the same as that between thegram and the cubic centimeter EXAMPLE 1 50 parts by weight ofa-phenyl-a-piperidyl-(Z)-acetic acid methyl ester hydrochloride, havinga content of about 20 percent of b-racemate are dissolved in a little-water, the solution covered with a layer of ether and 1.5 equivalentsof aqueous 50 percent caustic potash solution added thereto. layer, theaqueous layer is extracted twice with ether and After the separation ofthe ether -meric a-phenyl-a-piperidyl-(2)-acetic acid racemates,

which mixture becomes solid after a few hours standing at 20 C. It isdiluted with 110 parts by volume of water and brought to pH, 6.0 with137 parts by volume of 2 N- sulfuric acid. The b-racemate ofa-phenyl-a-piperidyl- (2)-acetic acid is precipitated while thea-racemate remains in solution. The precipitate is granular and wellsuited to filtration with suction. After several hours drying at 100 C.it weighs 24.2 parts by weight and consists of pure b-racemate ofa-phenyl-a-piperidyl-(Z) -acetic acid.

Re-esterification to b-racemates of a-phenyl-a-piperidyl- (2)-aceticacid esters and the formation of the corresponding hydrochlorides can becarried out by conventional methods.

As an example, the methyl ester hydrochloride is obtained by suspensionof 1 part by weight of the bracemate of u-phenyl-u-piperidyI-(Z)-aceticacid in 3.5 .parts by volume of methanol and by boiling for 2 hoursunder reflux with passage of dry hydrogen chloride gas. After thecooling of the solution, the b-racemate ofuphenyl-a-piperidyl-(2)-acetic acid methyl ester hydrochloridecrystallises in fine prisms of melting point 208- 209 C. The solubilityat 20 C. in methanol is 164 grams per liter.

The b-racemate of the butyl ester hydrochloride is ob- .tained in ananalogous manner by stirring for 2 hours one part by weight ofb-racemate of a-phenyl-a-piperidyl-(2)-acetic acid in 4 parts by volumeof n-butanol in a stream of hydrogen chloride at 80 C. The b-racemate ofthe a-phenyl-a-piperidyl-(2)-acetic acid butyl ester hydrochloride,which crystallizes on cooling, can be recrystallized from acetone andmelts at 165 C.

The a-phenyl-a-piperidyl-(2)-acetic acid methyl ester hydrochloride,used as starting material, can be obtained in the following manner:

75 parts by weight of a-phenyl-a-pyridyl-(2)-acetamide, are hydrogenatedin a solution of glacial acetic acid in the presence of 1 part by weightof platinum oxide (according to Adams) at 40 C. 24.000 parts by volumeof hydrogen and 760 mm.) are absorbed in 26 hours. The acetic acid isevaporated and, after the addition of water, the piperidine base isprecipitated by means of caustic soda. Recrystallized from ethyl acetateand dried for 12 hours in vacuo at 70 C. and 12 hours at 120 C., theamide melts at 173 C. Yield 70 parts by weight.

parts by weight of ot-phenyl-a-piperidyl-(2)-acetamide are refluxed with100 parts by volume of concentrated hydrochloric acid for 9 hours. Uponcooling the crystalline hydrochloride of the a-phenyl-a-piperidyl-(Z)-acetic acid precipitates. It is recrystallized from methyl alcohol andhas a decomposition point of 248 C.,

1 part by weight of this hydrochloride is suspended in 3.5 parts byvolume of methanol and boiled for 2 hours under reflux with passage ofdry hydrogen chloride gas. After the cooling of the solution theracemate mixture 4 of the u-phenyl-a-piperidyl-(2)-acetic acid methylester hydrochloride crystallizes. The melting point of the mixturevaries between 200206 C.

EXAMPLE 2 116 parts by weight of the a-racemate ofa-phenyl-apiperidyl-(2)-acetic acid hydrochloride are boiled underreflux for 5 hours with 2000 parts by weight of potassium hydroxidedissolved in 2000 parts by volume of water. -The whole reaction solutionis then neutralized with hydrochloric acid to pH=6.0 with simultaneousdilution with water to 10.000 parts by volume. A granuular precipitateis deposited which consists of a mixture of potassium chloride and theb-racemate of a-phenylaxpiperidyl-(2)-acetic acid. The potassiumchloride can be removed by washing with water. In this manner 69 partsby weight of b-racemate. of nt-phenyl-a-piperidyl-(2)- acetic acid areobtained, which can be esterified by the method described in Example 1.It is also possible, however, to effect the esterification using themixture of potassium chloride and b-racemate.

The a-racemate of a-phenyl-a-piperidyl-(2)-acetic acid hydrochloride,which is used as starting material, can be obtained, for example, asfollows:

50 parts by weight of a-phenyl-a-piperidyl-(2)-acetic acid methylesterhydrochloride with a content of about 20 percent of b-racemate aretreated with caustic potash solution as described in Example 1. Theseparated mixture of the potassium salts of the stereoisomericint-phenyla-piperidyl-(2)-acetic acid racemates is diluted with parts byvolume of water and brought to pH=6 with 137 parts by volume of 2N-hydrochloric acid. The precipitated b-racemate is filtered withsuction and the mother liquor evaporated to dryness. The residue isrecrystallized from 6 N-hydrochloric acid. In this manner purea-racemate of a-phenyl-a-piperidyl-(Z)-acetic acid hydrochloride isobtained.

It can be esterified in the same manner as the b-racemate by boiling itin methanol with passage of hydrogen chloride gas. The resultinga-racemate of a-phenyl-apiperidyl-(2)-acetic acid methyl esterhydrochloride has a melting point of 207208 C. and its solubility at 20C. in methanol is 234 grams per liter.

EXAMPLE 3 25 parts by weight of crude a-phenyl-a-piperidyl-(Z)-acetamide, with a content of about 30 percent of b-racemate, are boiledfor 10 hours under reflux with 25 parts by weight of potassium hydroxidedissolved in 50 parts by volume of water. After cooling, 23.5 parts byweight are deposited of a racemate mixture ofa-phenyl-apiperidyl-(2)-acetamide with an increased content ofbracemate, which mixture is filtered with suction, washed with a littlecold water and hydrolyzed to a-phenyl-apiperidyl-(2)-acetic acid by 6hours boiling with 47 parts by volume of 40 percent sulfuric acid. Thehydrolysis solution is brought to pH=6.0 with caustic potash solutionwith simultaneous dilution with water to 400 parts by volume. 19 partsby weight are deposited of b-racemate of a-phenyl-a-piperidyl-(2)-aceticacid, which can be esterified as described in Example 1. Theaphenyl-a-piperidyl-(2)acetamide is prepared as described in Example 1.

EXAMPLE 4 500 parts by weight of crude a-phenyl-a-piperidyl-(2)-acetamide with a content of a-racemate of 68 percent, are dissolved in2000 parts by volume of absolute ethyl alcohol, the solution treatedwith dry hydrogen chloride gas and the whole allowed to stand for 2hours at 510 C. 425 parts by weight of nearly pure a-racemate ofaphenyl-a-piperidyl (2) acetamide hydrochloride (solubility at 25 inabsolute ethanol=4 grams per liter) crystallize out. This product isboiled under reflux for '16 hours-with 425 parts by weight of potassiumhydroxide dissolved in 850 parts by volume of water. The

racemate. mixture of e-phenybarpiperidyhtzyacetamide, which precipitateson cooling, together with the: ev'apo: ration residue fromthe above.obtained alcoholicmother liquor from. the a-racemate and which.consistsv of practically; pure b-racemate of the hydrochloride ofcit-phenyla-piperidyl-(2,)-acetamide (solubility at 25 in absoluteethanol=185 grams per liter) is hydrolyzed by boiling for 6' hours with1300parts by volume of 40 percent sulfuric acid. By dilution andneutralization of the hydrolysis solution to PH=6L a precipitate isobtained of bracemate of u-phenyI-u-piperidyI-(Z)-acetic acid whichisolated as described in Example 1. Yield 382 parts by weight.

The a-phenylawpiperidyl-(2).-acetamide used as starting material isobtained by the procedure described in Example 1.

EXAMPLE 5 t 40 parts by weight of the crude a-phenyl-a-piperidyl-(2)-acetamide as used in Example 4 are stirred for 2 hours at 100 C.with 200 parts by volume of a 40 percent solution of trimethylbenzylammonium hydroxide in water. Thereupon, with cooling, the Whole isbrought to pH=9.9 with 6 N-hydrochloric acid and the solutionexhaustively extracted with ethylene chloride. The ethylene chlorideresidue is hydrolyzed with 40 percent sulfuric acid in a manneranalogous to that described in Example 4 and the hydrolysis solutionalso worked up in an analogous manner to that described in the saidexample. In this manner 19.9 parts by weight of bracemate ofa-phenyl-a-piperidyl-(2)- acetic acid are obtained.

EXAMPLE 6 11 parts by weight of the laevo-rotary 'a-isomer ofocphenyl-a-piperidyl-(2)-acetamide-herein before called a antipode-,having a specific rotation [a] =-68 (as 1 percent solution in 60 percentethanol) and a solubility in ethyl acetate at 25 of 20.5 grams perliter--melting points 162-l63 C.are refluxed for 6 hours with 12 partsof potassium hydroxide, dissolved in 12 parts by volume of Water. Aftercooling, 10.5 parts by weight of a mixture of a -antipode and b-antipode of the aphenyl-u-piperidyl-(2)-acetamide precipitate. Theprecitate is suction-filtered, washed with a small amount of cold water,and dried for half an hour at 70 C. under reduced pressure. The materialthen has a specific rotation [a] =+41 (as 1 percent solution in 60percent ethanol). By recrystallization from 350 parts by volume of ethylacetate there is obtained a first main fraction of 4.9 parts by weightof b -antipode, having a specific rotation [a] =|65 (as 1 percentsolution in 60 percent ethanol) and a solubility in ethyl acetate at25": 8.7 grams per liter. By systematic fractional crystallization it ispossible to regenerate from the mother liquors further quantities of bantipode, in addition to 2.5 parts by weight of the originally used a-antipode. Yet it is preferable to subject the combined mother liquorproducts of the first b antipode crystallization to a further alkalinetreatment, whereupon a main fraction of pure b -antipode can beseparated, again by a single crystallization operation from ethylacetate. This procedure is repeated until practically the entirequantity of a -antipode is converted into the b -antipode of theaphenyl-a-piperidyl-(2)-acetamide (melting point=170 171C.). 7

From 4.5 parts by weight of this b -antipode of theaphenyI-a-piperidyI-(Z)-acetamide there are obtained by refluxing for 6hours with 14.5 parts by volume of 6 N hydrochloric acid and subsequentrecrystallization at 20 C. 5.0 parts by weight of the b -antipode ofa-phenyl-apiperidyl-(2)-acetic acid hydrochloride having a specificrotation [a] =|-63 (as 1 percent solution in water) and a melting point207 --208 C.

4.5 parts by weight of this substance are dissolved in 2 parts by volumeof methanol and refluxed for 2 hours w ile in rodu i g y hy n, hl ri egas- On 0001- ing, 3.8 parts by weight of the b -antipode of a-phenyia-piper-idyl-(2) -acetic acid-methyl esterahydrochloride having aspecific rotation. [al =:+89' (as 1 percent solution in methanol) andmel ing Point 205 -206 'C. ale. obtained.

' The a antipode of a-phenyl-a-piperidyl (2) acetamide used as startingmaterial isv obtained inv the following manner:

109 parts by weight of a-racemate of aphenyl-a-piper idyl-(2)-acetamide(melting point 167 168 C.) are dissolved in 2500 parts by volume of 96percent ethanol the boilingsolution mixed with a boiling solution of.75, parts by weight of l-tartaric acidin 2500 parts by volume of 96percent ethanol. The mixture is allowed to. standat 20 C. for 15 hoursduring which 112parts by weight. of the acid a-phenyleapiperidyl-(2)-acetamide :tartrate crystallize; this salt contains the aantipo'de irrenriched form owing to itshigherspeed of crystallization.The acid tartrate is dissolved in 500 parts iby volume of water, theamide is precipitated with 1.1 equivalents of 10 N-caustic sodasolution; the preparation and crystallization of the salt by the sameprocedure is repeated twice with correspondingly smaller amounts ofl-tartaric acid and solvent. The crude a -antipode is crystallized fromethyl acetate to obtain 35 parts by weight of the pure .a -antipode ofa-pheny-l-a-piperidyl- (2)-acetamide used for the rearrangementreaction.

The a -antipode of a-phenyI-uiperidyl-(Z)aacetamide can be obtained fromthe a-racernate by the same procedure using a d-tartaric acid. Thisantipode can be converted into the b -antipode of ot-phenyl-a-piperidyl-(2)-acetamide and subsequently into the b -antipode ofu-phenyl-a-piperidyl-(2)acetic acid methyl ester hydrochloride, having aspecific rotation [u] =89 C. (as 1 percent solution in methanol).

From the b-racemates and b-antipodes obtained as described in theseexamples pharmaceutical preparations can be obtained in the usualmanner, eg.

(A) Tablets One tablet contains To prepare the tablets, the abovementioned b-racemate, lactose and calcium triphosphate are mixedtogether. Gelatine is dissolved in water and part of the wheat starch ispasted with the solution. The racemate mixture is treated 'with thepaste, the remaining wheat starch is added and the product granulatedand dried. A lubricant is added and the .g-ranuiate pressed intotablets.

(B) Ampoule solution One ampoule contains 20 mg. b-racemate ofu-phenylu-piperidyl-(2)-acetic acid methylester hydrochloride; 5 mg.calcium levulinate and distilled water to make up 1 cc.

Preparation.The bracemate and calcium levulinate are dissolved in therequired quantity of distilled water, the solution is filtered understerile conditions, and the .ampoules filled, aseptic precautions beingtaken.

(C) Dry ampoules One ampoule contains 20 :mg. of b-racemate ofaphenyl-a-piperidy1-(2)-acetic acid methylester hydrochloride, and 5 mg.of calcium levulinate.

'Rreparation.-A solution of the b-racemate. prepared as indicated underB is filtered under sterile conditions, filled into ampoules, andsubjected to freeze drying, aseptic precautions 'being taken. The driedampoules are sealed in the usual manner. H

In the same way, preparations with the b antipode bfu-phenyl-a-piperidyl-(2)eactic acid methyl ester hydrochloride can bemade.

What is claimed is: j '1. The .b -antipode form ofa-pheny1-a-piperidyl-(2)- acetic acid lower alkyl ester tree from the b-antipode form. r .2. The b -antipode form of a-phenyl-a-piperidyl-(2)-acetic acid methyl ester free from the b -antipode form. 3. The b-antipode form of a-phenyl-a-piperidyl-(2).- acetic acid methyl esterhydrochloride tree from the b antipode form.

8 4. The b antipode form of a-phenyl-a-piperidyl-(b acetic acid firee'drom the b antipode form.

5. The b -antip'ode form of a-phenyl-u-piperidyl-(2)- acetic acid amidetree atrom the b -antipode form.

6. The b -antipode form of a-phenyl-a-piperidyl-(2)- acetic acidhydrocloride free from the b -antipode form.

References Cited in the file of this patent UNITED STATES PATENTS2,507,631 Hartmalm at ail. May 16, 1950 2,774,789 Tullar Dec. 18, 19562,838,519 Rometsch June 10, 1958 OTHER REFERENCES Crook et .al.: J. Am.Chem. Soc., vol. 52, pp, 4006.- 4010 (1930).

Fieser and Fieser: Org. Chem, 3rd ed., pp. 264267 (1956).

UNITED STATES PATENT OFFICE CERTIFICATION OF CORRECTION Patent.v No.$957,880 October 25, 1960 Rudolf Rometsch It is hereby certified thaterror eppears in the above numbered patent requiring correction and thatthe said Letters Patent should read as corrected below. v

Column 6, line 1, for "2'" first occurrence, read 12 line 32, after"using? strike out, "a"; line 35,

for "(2.)acetic" read (2)acetic column 7', line 11, for "actic" readacetic Signed and sealed this 6th day of June 1961.,

(SEAL) Attest:

ERNEST W. SWIDER DAVID L. LADD Attesting Officer Commissioner of Patents

1. THE B1-ANTIPODE FORM OF A-PHENYL-A-PIPERIDYL-(2)ACETIC ACID LOWERALKYL ESTER FREE FROM THE B2-ANTIPODE FORM.
 4. THE B1-ANTIPODE FORM OFA-PHENYL-A-PIPERIDYL-(2) ACETIC ACID FREE FROM THE B2-ANTIPODE FORM.